Cell differentiation is a process in which a precursor cell develops into a new type of cell in response to specific internal or external stimuli. The lon term goal of this proposal is to understand how to control low rates of terminal cell differentiatin such are observed in vivo to maintain tissue size under normal conditions. Adipocyte differentiation, or the conversion of proliferating precursor cells into non-dividing fat cells or adipocytes capable of accumulating lipid, is one of the most accessible experimental systems for investigating terminal differentiation in mammalian cells. Understanding adipogenesis also has great medical relevance since defects in adipogenesis underlie the current worldwide epidemics in obesity, insulin resistance, diabetes, and cardiovascular disease. Computational modeling, quantitative mass spectrometry and single-cell microscopy will be used to identify and understand the system architecture and molecular mechanisms that cells use to have sufficient cell-to-cell variability in protein expression (noise) required to regulate small fractional rates f cell differentiation while at the same time allowing for controlled and stable terminal cell differentiation. The outcome of this work will be a fundamental understanding of the system architecture and molecular mechanisms that can control small fractional differentiation rates, opening up new venues of therapeutic intervention for the defective adipocyte differentiation underlying insulin resistance and type 2 diabetes. The results of this study will likely have broad relevance for all cell differentiation processes and may help in developing novel approaches to restore defective or aging cardiac, neuronal, hematopoietic, and other tissues.